Pyrrolotriazolopyrimidinone derivatives

ABSTRACT

This invention relates to new therapeutically useful 8-(disubstituted)phenyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one and 8-phenyl-6,9-dihydro-5H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one derivatives of formula (I): wherein: —X—C—Y— represents (a) or (b) to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their medical uses as potent and selective inhibitors of phosphodiesterase 5 (PDE 5).

[0001] This invention relates to new therapeutically usefulpyrrolotriazolopyrimidinone derivatives, to processes for theirpreparation and to pharmaceutical compositions containing them.

[0002] We have now found that certain8-(disubstituted)phenyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-oneand 8-phenyl-6,9-dihydro-5H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one derivatives are potent andselective inhibitors of phosphodiesterase 5 (PDE 5), and have efficacyin the treatment of angina, hypertension, congestive heart failure,stroke, asthma, male erectile dysfunction, female sexual dysfunction,premature labour, dysmenorrhea, BPH, incontinence, glaucoma andirritable bowel syndrome.

[0003] Accordingly, the present invention provides compounds which are8-phenylpyrrolotriazolopyrimidine derivatives of formula (I):

[0004] wherein: —X—C—Y— represents

[0005] as in formula (II)

[0006] or —X—C—Y— represents

[0007] as in formula (III)

[0008] R¹, R² and R³ each independently represent: hydrogen; an alkylgroup which is unsubstituted or substituted by hydroxy, alkoxy,alkylthio, amino, mono- or di-alkylamino, hydroxycarbonyl,alkoxycarbonyl, acylamino, carbamoyl or alkylcarbamoyl groups; or agroup of formula

—(CH₂)_(n)—R⁷

[0009] wherein n is an integer from 0 to 4 and R⁷ represents: acycloalkyl group which may be unsubstituted or substituted by one ormore halogen atoms or alkyl, hydroxy, alkylenedioxy, alkoxy, amino,mono- or di-alkylamino, alkylamido, nitro, cyano or trifluoromethylgroups; a phenyl group which may be unsubstituted or substituted by oneor more halogen atoms or alkyl, hydroxy, alkylenedioxy, alkoxy, amino,mono- or di-alkylamino, nitro, cyano or trifluoromethyl groups; or a 3to 7-membered ring comprising from 1 to 4 heteroatoms selected fromnitrogen, oxygen and sulphur, which ring may be unsubstituted orsubstituted by one or more halogen atoms or hydroxy, alkoxy, phenyl,alkoxycarbonyl, amino, mono-alkylamino, di-alkylamino or hydroxycarbonylgroups or one or more alkyl groups which may be unsubstituted orsubstituted by one or more halogen atoms or hydroxy, alkoxy,hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, mono- or di-alkylamino orhydroxycarbonyl groups;

[0010] either R⁴ and R⁵ together with the nitrogen atom to which theyare attached form a 3 to 7-membered ring comprising a total of from 1 to4 heteroatoms selected from nitrogen, oxygen and sulphur, which ring maybe unsubstituted or substituted by one or more halogen atoms or hydroxy,oxoalkyl, carbamoyl, hydroxycarbonyl, alkoxycarbonyl, trifluoroacetyl,amino, mono- or di-alkylamino groups and/or an alkylene group and/or oneor more alkyl groups, wherein said alkylene group and said alkyl groupsmay in turn be unsubstituted or substituted by one or more hydroxy,alkoxy, hydroxyalkoxy, amino or mono- or di-alkylamino groups, or

[0011] R⁴ and R⁵ independently represent hydrogen, an amidino group oran alkyl, alkenyl or alkynyl group which may be unsubstituted orsubstituted by one or more halogen atoms or hydroxy, alkoxy, alkylthio,amino, mono- or di-alkylamino groups, or

[0012] R⁴ represents hydrogen or an alkyl group and R⁵ represents agroup of formula —(CH₂)_(n)—R⁷ wherein n and R⁷ are defined above,

[0013] R⁶ represents a hydrogen or halogen atom, or a nitro oralkoxycarbonyl group, or an alkyl group which is unsubstituted orsubstituted by one or more hydroxy, alkoxy, alkylthio, amino, mono- ordi-alkylamino, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl oralkylcarbamoyl groups,

[0014] or a pharmaceutically acceptable salt thereof.

[0015] When R⁴ and R⁵, together with the nitrogen atom to which they areattached, form a 3 to 7-membered ring, said ring may be unsubstituted orsubstituted by one or more halogen atoms or hydroxy, oxoalkyl,carbamoyl, hydroxycarbonyl, alkoxycarbonyl, trifluoroacetyl, amino,mono- or di-alkylamino groups or an alkylene group or one or more alkylgroups which may in turn be unsubstituted or substituted by one or morehydroxy, alkoxy, hydroxyalkoxy, amino or mono- or di-alkylamino groups.

[0016] The alkyl groups and alkyl moieties such as those present in thealkoxy, alkylcarbamoyl, mono- or di-alkylamino, carbamoyl, alkylthio,oxoalkyl, alkylenedioxy, alkylamido and alkoxycarbamoyl groups mentionedherein, unless otherwise stated, are usually “lower” alkyl, that iscontaining from 1 to 6 particularly from 1 to 4 carbon atoms, thehydrocarbon chain being branched or straight. Preferred alkyl groups,and where relevant alkyl moieties, include methyl, ethyl, n-propyl,i-propyl, n-butyl, sec-butyl, i-butyl and t-butyl. Alkenyl and alkynylgroups mentioned in relation to formula (I) preferably have from 2 to 6carbon atoms, most preferably from 2 to 4 carbon atoms. Acylamino groupsmentioned in relation to formula (I) above preferably are of the formula—NC(O)R wherein R is an alkyl group as defined above.

[0017] Where an alkyl, alkenyl or alkynyl group, heterocyclic ringstructure or moiety is described as being substituted by one or moresubstituents this preferably means from 1 to 3 substituents, morepreferably one or two substituents.

[0018] The halogen atoms mentioned in relation to the groups R⁴ to R⁷are selected from fluorine, chlorine, bromine and iodine and mostpreferably from bromine, chlorine and fluorine atoms.

[0019] In substituent groups of formula

—(CH₂)_(n)R⁷

[0020] n may represent 0, 1, 2, 3, or 4, preferably 0, 1, 2 or 3.

[0021] The cycloalkyl group mentioned in relation to the group R⁷ ispreferably a C₃₋₁₀ cycloalkyl group, more preferably a C₃₋₇ cycloalkylgroup such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylgroup. The cycloalkyl-alkyl groups within the definition —(CH₂)_(n)—R⁷preferably include cyclopropylmethylene, cyclopropylethylene,cyclopentylmethylene, cyclopentylethylene, cyclohexylmethylene andcyclohexylethylene. In compounds of the invention wherein the cycloalkylgroup is substituted, preferred substituents include acetamido and mono-and di-alkylamino, most preferably mono- or di-ethylamino groups. Thesubstituent group may be at any substitutable position of the cycloalkylring. Preferably the cycloalkyl ring is substituted at the 1-position.

[0022] When R⁷ represents a phenyl group substituted by one or morehalogen atoms or alkyl, hydroxy, alkoxy, amino, mono- or dialkyl amino,nitro, cyano or trifluoroalkyl groups, the phenyl ring may besubstituted by 1, 2, 3, 4 or 5 substituents, preferably 1, 2 or 3substituents, most preferably one or two substituents, each beingindependently selected from the possible substituents set out above.That is to say, the phenyl group (attached through its 1-position) maybe substituted at any of the remaining positions, that is to say the 2,3, 4, 5 or 6-positions. A phenyl group having more than one substituentmay be substituted at any combination of positions. For example a phenylgroup having two substituents may be substituted at the 2 and 3, 2 and4, 2 and 5, 2 and 6, 3 and 4 or 3 and 5 positions. If the phenyl groupis substituted bygone or more alkylene dioxy groups then they arepreferably present on any adjacent pair of substitutable positions.

[0023] When R⁷ represents a 3-7 membered ring in accordance with formula(I), the ring may be unsaturated or saturated and may represent forexample a piperidyl, pyrrolidyl, azetidinyl, aziridyl, piperazinyl,morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl, imidazolidinyl,pyrazolinyl, indolinyl, isoindolinyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl,quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, quinuclidinyl,triazolyl, pyrazolyl, tetrazolyl, tetrahydrofuranyl or thienyl group,which group may be substituted or unsubstituted.

[0024] In preferred compounds of the invention R¹, R² and R³independently represent a group of formula

—(CH₂)_(n)R⁷

[0025] wherein R⁷ represents a 3 to 7-membered heterocyclic ring, R⁷ isa pyridyl, piperidyl, piperazinyl, morpholinyl, triazolyl or tetrazolylgroup or hydrogen or an unsubstituted alkyl, group selected from methyl,ethyl, n-propyl, -1-propyl, n-butyl, sec-butyl and t-butyl.

[0026] In preferred compounds of the invention R1 represents: hydrogen;a C₁-C₄ alkyl group; or a group of formula

—(CH₂)_(n)R⁷

[0027] wherein n is 0, 1 or 2 and R⁷ represents phenyl, pyridyl ormorpholinyl. Most preferably R¹ is a methyl group.

[0028] In preferred compounds of the invention R² represents: a C₁-C₅alkyl group especially a C₁-C₄ alkyl group; a substituted C₁-C₄ alkylgroup; a C₃₋₁₀ cycloalkyl group; or a group of formula

—(CH₂)_(n)R⁷

[0029] wherein n is 0, 1 or 2 and R⁷ represents an unsubstituted orsubstituted phenyl or pyridyl group. Most preferably R² is an n-propylgroup.

[0030] In preferred compounds of the invention R³ represents: a C₁-C₄alkyl group; a C₃₋₁₀ cycloalkyl group; or a group of formula

—(CH₂)_(n)R⁷

[0031] wherein n is 0, 1 or 2 and R⁷ represents an unsubstituted orsubstituted phenyl or pyridyl group. Most preferably R³ is an ethyl orn-propyl group.

[0032] For compounds of the invention wherein R⁴ and R⁵ together withthe nitrogen atom to which they are attached form a 3 to 7-membered ringcomprising a total of from 1 to 4 heteroatoms, the ring may be saturatedor unsaturated and is preferably selected from a piperidyl, pyrrolidyl,azetidinyl, aziridyl, piperazinyl, [1,4]diazepan-1-yl, morpholinyl,thiomorpholinyl, pyrrolyl, pyrazolyl, imidazolyl, imidazolidinyl,pyrazolinyl, indolinyl or isoindolinyl group, said group beingunsubstituted or substituted as defined above. For example, said groupmay be unsubstituted or substituted by an alkylene group and/or from 1to 3 groups independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl,carbamoyl, amino, di-C₁-C₄-alkylamino, (2-hydroxyethyl)methylamino,hydroxyl, 2,2,2-trifluoroethanoyl, 2,2,2-trifluoroethyl, carbaldehydegroups and hydroxyalkyl groups, alkoxycarbonyl groups, alkoxyalkylgroups and hydroxyalkoxyalkyl groups wherein the alkyl moieties containfrom 1 to 4 carbon atoms, and wherein said alkylene group may in turn beunsubstituted or substituted by one or more hydroxy, alkoxy,hydroxyalkoxy, amino or mono- or di-alkylamino groups. Typically saidgroup is an alkylene group or from 1 to 3 groups independently selectedfrom C₁-C₄ alkyl, C₂-C₄ alkenyl, carbamoyl, amino, di-C₁-C₄-alkylamino,(2-hydroxyethyl)methylamino, hydroxyl, 2,2,2-trifluoroethanoyl,2,2,2-trifluoroethyl, carbaldehyde groups and hydroxyalkyl groups,alkoxycarbonyl groups, alkoxyalkyl groups and hydroxyalkoxyalkyl groupswherein the alkyl moieties contain from 1 to 4 carbon atoms.

[0033] It is to be understood that when the substituent is an alkylenegroup it is attached to the heterocyclic ring at any two substitutablepositions which may be adjacent or not adjacent to each other. When thesubstitutable positions are not adjacent to each other, the alkylenegroup forms a bridging group. The alkylene group preferably has from 1to 5 carbon atoms.

[0034] In preferred compounds of the invention the ring formed by R⁴, R⁵and the nitrogen atom to which they are attached is a substituted orunsubstituted piperidyl, pyrrolidyl, piperazinyl, [1,4]diazepan-1-yl,morpholinyl, pyrazolyl, azetidinyl, diazabicyclo[2.2.1]hept-2-yl orhexahydropyrrolo[2,1-a]pyrazinyl group. Preferred substituent groups areone or more groups selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, carbamoyl,amino, di-C₁-C₄-alkylamino, (2-hydroxyethyl)methylamino, hydroxyl,2,2,2-trifluoroethanoyl, 2,2,2-trifluoroethyl, carbaldehyde (formyl)groups and hydroxyalkyl groups, alkoxycarbonyl groups, alkoxyalkylgroups and hydroxyalkoxyalkyl groups wherein the alkyl moieties containfrom 1 to 4 carbon atoms, and C₁₋₄ alkylene groups wherein the alkylenegroup may be unsubstituted or substituted by a hydroxy group. Typically,the substituent groups are selected from C₁₋₄ alkyl, C₂-C₄ alkenyl,carbamoyl, amino, di-C₁-C₄-alkylamino, (2-hydroxyethyl)methylamino,hydroxyl, 2,2,2-trifluoroethanoyl, 2,2,2-trifluoroethyl, carbaldehyde(formyl) groups and hydroxyalkyl groups, alkoxycarbonyl groups,alkoxyalkyl groups and hydroxyalkoxyalkyl groups wherein the alkylmoieties contain from 1 to 4 carbon atoms.

[0035] Most preferably R⁴ and R⁵ together with the nitrogen atom towhich they are attached represent a 4-hydroxy7 piperidyl,4-carbamoylpiperidyl, 3-carbamoylpiperidyl, piperazinyl,4-methylpiperazinyl, 4-ethylpiperazinyl, 4-formylpiperazinyl,[1,4]-diazepan-1-yl, 4-methyl-[1,4]-diazepan-1-yl,4-(2-hydroxyethyl)piperazinyl, 4-[2-(2-hydroxyethoxy)ethyl]piperazinyl,morpholinyl, aminopyrazolyl, diazabicyclo[2.2.1]hept-2-yl,5-methyldiazabicyclo[2.2.1]hept-2-yl, 4-ethoxycarbonylpiperazine,4-piperazine carbaldehyde,5-(2-hydroxyethyl)-diazabicyclo[2.2.1]hept-2-yl, 3(S)-methylpiperazinyl,3(R)-methylpiperazinyl, (3,5)-3,5-dimethylpiperazinyl,(3R,5S)-3,5-dimethylpiperazinyl, (2R,5S)-2,5-dimethylpiperazinyl,(2S,5R)-2,5-dimethyl piperazinyl, 3-dimethylaminoazetidinyl,3-dimethylaminomethylazetidinyl, 4-allylpiperazinyl,4-propylpiperazinyl,hexahydropyrrolo[1,2-a]pyrazin-2-yl,(3R,5S)-3,4,5-trimethylpiperazinyl,4-(0.2-methoxyethyl)-piperazinyl, 4-(2-hydroxyethyl)[1,4]diazepan-1-yl,4-(2-hydroxy-1-methylethyl)piperazinyl,4-(2-hydroxy-1,1-dimethylethyl)piperazinyl,4-(2,2,2-trifluoroethyl)-piperazinyl, 4-(3-hydroxypropyl)piperazinyl,4-(isopropyl) piperazinyl, 4-(2-ethoxyethyl)piperazinyl,4-(2,2,2-trifluoroethanoyl)piperazinyl, 3-hydroxyazetidinyl,3-(2-hydroxyethyl)methylaminoazetidinyl, 4-(2-hydroxyethyl)-piperidyl,hexahydropyrrolo[1,2-a]pyrazinyl,3-methylhexahydropyrrolo[1,2-a]pyrazinyl,7-hydroxyhexahydropyrrolo[1,2-a]pyrazinyl or5-methyl-2,5-diazabicyclo[2.2.1]heptanyl group.

[0036] For compounds of the invention wherein R⁴ and R⁵ independentlyrepresent hydrogen, an amidino group or an alkyl, alkenyl or alkynylgroup which may be unsubstituted or substituted by one or more hydroxy,alkoxy, alkylthio, amino, mono- or di-alkylamino groups, preferably R⁴and R⁵ independently represent hydrogen or a propynyl group, an amidinogroup or a C₁-C₄ alkyl group which is unsubstituted or substituted by ahydroxy, methyl or dimethylamino group. Most preferably R⁴ and R⁵independently represent hydrogen or a methyl, ethyl, propyl,2-hydroxyethyl, dimethylaminoethyl, propynyl, dimethylaminopropyl oramidino group.

[0037] In compounds of the invention wherein R⁵ is a group of formula

—(CH₂)_(n)R⁷

[0038] n is preferably 0, 1, 2 or 3 and R⁷ is preferably a group R⁸which represents a piperidyl, pyrrolidyl, azetidinyl, aziridyl,piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl,imidazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl,indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,quinuclidinyl, triazolyl, pyrazolyl, triazolyl, tetrazolyl or thienylgroup, which group may be substituted or unsubstituted. Substituents arepreferably selected from alkyl, hydroxy, alkoxy, mono- or dialkylamino,acetamide, hydroxyalkyl, alkoxyalkyl, oxoalkyl, phenyl, carbamoyl andalkylcarbamoyl groups. Methyl, hydroxy, methoxy, phenyl, ethylamino,diethylamino and acetamide groups being the most preferred substituents.Or R⁸ represents substituted cycloalkyl or phenyl group as definedabove. Most preferably R⁸ represents a pyridyl, piperidyl, piperazinyl,morpholinyl, triazolyl, tetrazolyl, pyrrolidinyl,1-ethylaminocyclohex-1-yl, 1-diethylaminocyclohex-1-yl,1-ethylaminocyclohept-1-yl, 1-diethylaminocyclohept-1-yl,3,4-dimethoxyphenyl, 1-methyl-4-phenylpiperidin-4-yl, imidazoyl,1-methylpiperid-4-yl, tetrahydrofuranyl,2,2,6,6,-tetramethylpiperid-4-yl, 4-hydroxypiperid-4-yl,1-acetamidocyclohept-1-yl, 1-methyl-3-azetidinyl or4-methylpiperazin-1-yl group.

[0039] In the most preferred compounds of the invention wherein R⁴ andR⁵ do not form a ring together with the nitrogen atom to which they areattached, R⁴ represents a hydrogen atom or a methyl, ethyl, propyl or2-hydroxyethyl group.

[0040] In the most preferred compounds of the invention wherein R⁴ andR⁵ do not form a ring together with the nitrogen atom to which they areattached, R⁵ represents a 2-hydroxyethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, amidino, propynyl, 1-pyridyl, 1-morphylinylethyl,1-piperidylethyl, 1-morpholinylpropyl, 1-pyrrolidylethyl,1-ethylaminocyclohexylmethyl, 1-ethylaminocycloheptylmethyl,1-diethylaminocyclohexylmethyl, 1-diethylaminocycloheptylmethyl,2-(3,4-dimethoxyphenyl)ethyl, 1-methyl-4-phenylpiperidin-4-ylmethyl,1R-[1,2,4]triazol-3-yl, pyridin-4-ylmethyl,2-pyridin-2-ylethyl,3-imidazol-1-ylpropyl, 1-methylpiperidin-4-yl, tetrahydrofuran-2-yl,tetrahydrofuran-2-ylmethyl, 2,2,6,6-tetramethylpiperidin-4-yl,2,2,6,6-tetramethylpiperidin-4-ylmethyl,1-acetamidocyclohept-1-ylmethyl, 1-methylazetidin-3-yl or4-methylpiperazin-1-yl group.

[0041] In preferred compounds of the invention R⁶ represents a fluorine,chlorine, bromine or hydrogen atom or a methyl, ethyl, n-propyl,n-butyl, methoxycarbonyl, ethoxycarbonyl, or nitro groups. Mostpreferably R⁶ represents a chlorine, bromine or hydrogen atom.

[0042] Particular individual compounds of the invention include:

[0043]8-[2-Ethoxy-5-(4-ethylpiperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0044]8-{2-Ethoxy-5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]phenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0045]8-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0046]8-[5-(4-Ethylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0047]8-[5-(4-methyl-[1,4]diazepane-1-sulfonyl)-2-propoxyphenyl3-6-propyl7-6,9-dihydro-5×-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0048]N-(2-Morpholin-4-ylethyl)-3-(5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxybenzenesulfonamide

[0049]8-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0050]8-[5-(4-methylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one 7-Chloro-8-

[0051][2-ethoxy-5-(piperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0052]7-Chloro-8-[2-ethoxy-5-(4-ethylpiperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0053]7-Chloro-8-[2-ethoxy-5-(4-methyl-[1,4]diazepane-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo(2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0054]3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5—pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-ethoxy-N-(2-morpholin-4-ylethyl)benzenesulfonamide

[0055]7-Chloro-8-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]phenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0056] 7-Chloro-8-{2-ethoxy-5-[4-(3-hydroxypropyl)piperazine-1-sulfonyl]phenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0057]7-Chloro-8-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0058]7-Chloro-8-[5-(3-dimethylaminomethylazetidine-1-sulfonyl)-2-ethoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-ethoxy-N-prop-2-ynylbenzenesulfonamide

[0059]8-[5-(4-Allylpiperazine-1-sulfonyl)-2-ethoxyphenyl]-7-chloro-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0060]7-Chloro-8-12-ethoxy-5-[4-isopropylpiperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrclo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0061]7-Chloro-8-(2-ethoxy-5-[4-(2-methoxyethyl)piperazine-1-sulfonyl]phenyl)-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0062]7-Chloro-8-[2-ethoxy-5-(4-propylpiperazine-1-sulfonyl)phenyl]-46-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0063]7-Chloro-8-[5-(3-dimethylaminoazetidine-1-sulfonyl)-2-ethoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e3[1,2,4] triazolo[4,3-c]pyrimidine-5-one

[0064]7-Chloro-8-{2-ethoxy-5-[4-(2-hydroxyethyl)-[1,4]diazepane-1-sulfonyl]phenyl}-6-propyl-6,9-dihydro-SH-pyrrolo[2,3-e][1,2, 4]triazolo[4,3-c]pyrimidine-5-one

[0065]7-Chloro-8-{2-ethoxy-5-[4-(2-ethoxyethyl)piperazine-1-sulfonyl]phenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c3pyrimidine-5-one

[0066]7-Chloro-8-[5-(piperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0067]7-Chloro-8-[5-(morfolino-4-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0068]7-Chloro-8-[5-(4-ethylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2, 4]triazolo[4,3-c] pyrimidine-5-one

[0069] 3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-y-)-N-(2-dimethylaminoethyl)-4-propoxybenzenesulfonamide

[0070]7-Chloro-8-[5-(4-methyl-[1,4]diazepane-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5S-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0071] 3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-(2-morpholin-4-ylethyl)-4-propoxybenzenesulfonamide

[0072]7-Chloro-8-{5-[4-(2-hydroxyethyl)piperazine-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0073]3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-(2-piperidin-1-ylethyl)-4-propoxybenzenesulfonamide

[0074] 3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo(2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-(3-morpholin-4-ylpropyl)-4-propoxybenzenesulfonamide

[0075]7-Chloro-8-{5-[4-(3-hydroxypropyl)piperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0076] 3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxy-IV-(2-pyridin-2-ylethyl)benzenesulfonamide

[0077]3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5R-pyrrolo[[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-(4-methylpiperazin-1-yl)-4-propoxybenzenesulfonamide

[0078]4-[3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxybenzenesulfonyl]piperidine-1-carboxaldehyde

[0079]7-Chloro-8-{5-[4-(2-methoxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0080]7-Chloro-8-[5-(4-methylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo(2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0081]7-Chloro-8-[2-propoxy-5-(4-propylpiperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0082]3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzenesulfonamide

[0083]3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxy-N-prop-2-ynylbenzenesulfonamide

[0084] 3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-methyl-A-(1-methylpiperidin-4-yl)-4-propoxybenzenesulfonamide

[0085]7-Chloro-8-{5-[4-(2-ethoxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0086]8-[5-(4-Allylpiperazine-1-sulfonyl)-2-propoxyphenyl]-7-chloro-6-propyl76,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0087]7-Chloro-8-[5-(4-isopropylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0088]7-Chloro-8-[5-(3-dimethylaminoazetidine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0089]3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-ethyl-4-propoxy-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide

[0090]3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N-dimethyl-4-propoxybenzenesulfonamide

[0091] 3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-(2-hydroxyethyl)-4-propoxybenzenesulfonamide

[0092] 3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-(2-dimethylaminoethyl)-N-methyl-4-propoxybenzenesulfonamide

[0093]7-Bromo-8-[2-ethoxy-5-(piperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0094]7-Bromo-8-[2-ethoxy-5-(4-ethylpiperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0095]3-(7-Bromo-5-oxo-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-ethoxy-N-(2-morpholin-4-ylethyl)benzenesulfonamide

[0096]7-Bromo-8-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]phenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyriiridine-5-one

[0097]7-Bromo-8-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0098]7-Bromo-8-[5-(4-ethylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0099]7-Bromo-8-[5-(4-methylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0100]3-(7-Bromo-5-oxo-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxy-N-prop-2-ynylbenzenesulfonamide

[0101]3-(7-Bromo-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N-dimethyl-4-propoxybenzenesulfonamide

[0102]7-Bromo-8-[5-(morfolino-4-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0103]7-Bromo-8-[5-(4-methyl-[1,4]diazepane-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0104]3-(7-Bromo-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-(2-morpholin-4-ylethyl)-4-propoxybenzenesulfonamide

[0105]7-Bromo-8-{5-[4-(2-ethoxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0106]3-(7-Bromo-5-oxo-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxy-Al-(2,2,6,6-tetramethylpiperidin-4-yl)benzenesulfonamide

[0107]3-(7-Bromo-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-methyl-N-(1-methylpiperidin-4-yl)-4-propoxybenzenesulfonamide

[0108]8-[5-(4-Allylpiperazine-1-sulfonyl)-2-propoxyphenyl]-7-bromo-6-propyl-6,9-dihydro-5q-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0109]7-Bromo-8-[5-(4-isopropylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0110]7-Bromo-8-[5-(3-dimethylaminoazetidine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0111]7-Bromo-8-[5-(3-dimethylaminomethylazetidine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0112]7-Bromo-8-(5-[4-(2-Hydroxyethyl)-[1,4]diazepane-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0113]7-Bromo-8-[5-(3,5-dimethylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0114]7-Bromo-8-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-oneand

[0115]7-Bromo-8-[5-(piperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0116]7-Chloro-8-[2-ethoxy-5-((S)-hexahydropyrrolo[1,2-a]pyrazine-2-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0117]7-Chloro-8-[2-ethoxy-5-((R)-hexahydropyrrolo[1,2-a]pyrazine-2-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0118] 7-Chloro-8-[2-ethoxy-5-((3R,8aS)-3-methylhexahydropyrrolo[1,2-a]pyrazine-2-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0119] 7-Chloro-8-[2-ethoxy-5-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,4,2-a]pyrazine-2-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0120] 7-Chloro-8-[2-ethoxy-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0121]7-Bromo-8-[5-((R)-hexahydropyrrolo[1,2-a]pyrazine-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0122] 7-Bromo-8-[5-((3R,8aS)-3-methylhexahydropyrrolo[1,2-a]pyrazine-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0123] 7-Bromo-8-[5-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0124] 7-Bromo-8-[5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0125]7-Iodo-8-[5-((S)-hexahydropyrrolo[1,2-a]pyrazine-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0126]7-Iodo-8-[5-((R)-hexahydropyrrolo[1,2-a]pyrazine-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e](1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0127] 7-Iodo-8-[5-((3R,8aS)-3-methylhexahydropyrrolo[1,2-a]pyrazine-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0128] 7-Iodo-8-[5-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0129] 7-Iodo-8-[5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-eJ[1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0130] Of outstanding interest are:

[0131]7-Chloro-8-[2-ethoxy-5-(4-methyl-[1,4]diazepane-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrol6[2,3-e](1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0132]7-Chloro-8-{2-ethoxy-5-[4-(2-ethoxyethyl)piperazine-1-sulfonyl]phenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0133] 7-Chloro-8-{5-[4-(3-hydroxypropyl)piperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0134] 3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-SH-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzenesulfonamide

[0135]8-[5-(4-Allylpiperazine-1-sulfonyl)-2-propoxyphenyl]-7-chloro-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e] [1,2,-]triazolo[4,3-c]pyrimidine-5-one

[0136] 3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-SH-pyrrolo [2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-(2-hydroxyethyl)-4-propoxybenzenesulfonamide

[0137] 7-Bromo-8-[5-(4-methylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo [2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0138]7-Bromo-8-{5-[4-(2-Hydroxyethyl)-[1,4]diazepane-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0139]7-Bromo-8-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0140]7-Bromo-8-[5-(piperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0141]7-Chloro-8-[2-ethoxy-5-(S)-hexahydropyrrolo[1,2-a]pyrazine-2-sulfonyl)phenyl]-6-propyl-6,9-dihydro-SH-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-c]pyrimidine-5-one and

[0142] 7-Chloro-8-[2-ethoxy-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one.

[0143] The present invention also provides processes for producing the8-phenyl-6,9-dihydro-5 h-pyrrolo[1,2,4]triazolo[4,3-c]pyrimidine-5-onederivatives of general formula (I). According to a further feature ofthe present invention, the8-phenyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-onederivatives of general formula (II) above are prepared by reaction ofthe corresponding sulphonyl chloride of formula (IV):

[0144] (wherein R¹, R², R³ and R⁶ are as hereinbefore defined) and thecorresponding amine (V):

[0145] (wherein R⁴ and R⁵ are as hereinbefore defined) The reaction ispreferably carried out in an organic solvent most preferably a polaraprotic organic solvent such as dioxane, methylene chloride ortetrahydrofuran, at a temperature from 10° C. to 40° C. and in thepresence of an organic base, most preferably an amine base such astriethylamine or polymer supported morpholine. The thus obtained8-phenyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one derivative is then preferably isolatedby the conventional methods known in the art.

[0146] In the case that R⁶ is hydrogen, the sulphonyl chloride (IV) ispreferably obtained from the corresponding compound of formula (VI):

[0147] (wherein R¹, R² and R³ are as hereinbefore defined), by reactionwith an excess of chlorosulphonic acid and optionally thionyl chloride,preferably under a nitrogen atmosphere and at a temperature from −5° C.to 10° C. and where the solvent is the same chlorosulphonic acid.

[0148] In the case that R⁶ is a chlorine atom, the correspondingsulphonyl chloride (IV) is preferably obtained from the correspondingcompound of formula (VI) by reaction with an mixture of chlorosulphonicacid and sulphuryl chloride, preferably under a nitrogen atmosphere andat a temperature from −5° C. to 10° C. and where the solvent is the samechlorosulphonic acid.

[0149] In the case that R⁶ is a bromine atom, the desired sulphonylchloride (IV) is preferably obtained from the corresponding sulphonylchloride (IV) where R⁶ is a hydrogen atom by reaction with bromine inglacial acetic acid at room temperature.

[0150] The8-phenyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-onederivatives of general formula (VI) are preferably prepared by reactionof a corresponding hydrazino derivative of formula (VII):

[0151] (wherein R², R³ and R⁶ are as hereinbefore defined) with thecorresponding carboxylic acid of the general formula (VIII):

R¹—COOH  (VIII)

[0152] (wherein R¹ is as hereinbefore defined) or a reactive derivativethereof. Preferred examples of a reactive derivative of the carboxylicacid (VIII) are the acid halide, orthoester or anhydride. The reactionmay be carried out in a solvent, preferably a polar aprotic solvent,such as N,N-dimethylformamide, dioxane, acetone or tetrahydrofuran, inthe presence of an organic base, preferably an amine base, such astriethylamine and at a temperature from 15° C. to the boiling point ofthe solvent.

[0153] The reaction can also be carried out in the absence of a solvent,in which case an excess of the carboxylic acid (VIII) or reactivederivative of the carboxylic acid (VIII) is used and the mixture isheated at a temperature from 40° C. to its boiling point. The thusobtained8-phenyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-onederivative is preferably then isolated by conventional methods known inthe art.

[0154] The hydrazinopurines of general formula (VII) are preferablyobtained by reaction of the 6-thioxopurines of the general formula (IX):

[0155] (wherein R², R³ and R⁶ are as hereinbefore defined) withhydrazine hydrate at a temperature from 80 to 150° C.

[0156] The 6-thioxo derivatives of general formula (IX) are preferablyobtained by reaction of the 6-phenylpyrrolopyrimidinedione of generalformula (X):

[0157] (wherein R², R³ and R⁶ are as hereinbefore defined) withphosphorus pentasulphide or Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide).The reaction is preferably carried out in a solvent, such as benzene,toluene, dioxane or pyridine, at a temperature from 40° C. to theboiling point of the solvent.

[0158] The 6-phenylpyrrolopyrimidinedione derivatives of general formula(X) are preferably prepared by a process comprising reaction of thecorresponding 6-methyl-5-nitrouracil of formula (XI):

[0159] (wherein R² is as hereinbefore defined), and the correspondingbenzaldehyde of formula (XII)

[0160] (wherein R³ is as hereinbefore defined), followed by reductivecyclization of the resulting 5-nitro-6-styryluracils by methods knownper se, e.g. C. E. Muller et al., J. Med. Chem. 1994, 37, 1526-1534 andreferences cited therein.

[0161] Substitutions other than chlorine or bromine atoms at R⁶ can beintroduced by reaction of the corresponding compound of general formula(II), (IV) or (VI) wherein R⁶ is a hydrogen atom or a suitably protectedversion of them with an appropriate electrophile.

[0162] According to a further feature of the present invention, the8-phenyl-6,9-dihydro-5R-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-5-onederivatives of general formula (III) above are prepared by reaction of acorresponding hydrazino derivative of formula (XIII):

[0163] (wherein R², R³, R⁴, R⁵ and R⁶ are as hereinbefore defined) withthe corresponding carboxylic acid of the general formula(VIII):

R¹—COOH  (VIII)

[0164] (wherein R¹ is as hereinbefore defined) or a reactive derivativethereof. Preferred examples of a reactive derivative of the carboxylicacid (VIII) are the acid halide, orthoester or anhydride. The reactionmay be carried out in a solvent, preferably a polar aprotic solvent,such as N,N-dimethylformamide, dioxane, acetone or tetrahydrofuran, inthe presence of an organic base, preferably an amine base, such astriethylamine and at a temperature from 15° C. to the boiling point ofthe solvent.

[0165] The reaction can also be carried out in the absence of a solvent,in which case an excess of the carboxylic acid (VIII) or reactivederivative of the carboxylic acid (VIII) is used and the mixture isheated at a temperature from 40° C. to its boiling point. The thusobtained8-phenyl-6,9-dihydro-5H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-5-onederivative is then isolated by usual methods known in the art.

[0166] The hydrazinopurines of general formula (XIII) are preferablyobtained by reaction of the 6-thioxopurines of the general formula(XIV):

[0167] (wherein R², R³, R⁴, R⁵ and R⁶ are as hereinbefore defined) withhydrazine hydrate at a temperature from 80 to 150° C.

[0168] The 6-thioxo derivatives of general formula (XIV) are preferablyobtained by reaction of the 6-phenylpyrrolopyrimidinedione of generalformula (XV):

[0169] (wherein R², R³, R⁴, R⁵ and R⁶ are as hereinbefore defined) withphosphorus pentasulphide or Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide).The reaction is preferably carried out in a solvent, such as benzene,toluene, dioxane or pyridine, at a temperature from 40° C. to theboiling point of the solvent.

[0170] The 6-phenyl-1,7-dihydropyrrolo[2,3-d]pyrimidine-2,4-dionederivatives of general formula (XV) are preferably prepared bycondensation of the corresponding 6-aminouracil of formula (XVI):

[0171] (wherein R² is as hereinbefore defined), with the correspondingbromoacetophenones of formula (XVII):

[0172] (wherein R³, R⁴ and R⁵ are as hereinbefore defined), by methodsknown per se, e.g. C. W. Noell et al., J. Heterocycl. Chem. 1964, 1,34-41, and H. Ogura et al., Chem. Pharm. Bull. 1972, 6, 404-408.

[0173] The 6-aminouracils of general formula (XVI) can be prepared fromthe corresponding N-substituted ureas by methods known per se, e.g. V.Papesch et al., J. Org. Chem. 1951, 16, 1879-90.

[0174] The bromoacetophenones (XVII) can be prepared from thecorresponding 2-alkoxyacetophenones (XVIII):

[0175] (wherein R³ is as hereinbefore defined), by chlorosulphonylation,reaction with the corresponding amine (V):

[0176] and further bromination of the resulting compound by methodsknown per se.

[0177] When the defined groups R¹ to R⁶ are susceptible to chemicalreaction under the conditions of the hereinbefore described processes orare incompatible with said processes, alternative processes can bereadily carried out utilising organic synthetic chemistry methods to,for example, protect functional groups and finally eliminate protectinggroups. Substitutions at R⁶ can be introduced by reaction of thecorresponding compound of general formula (III) wherein R⁶ is a hydrogenatom or a suitably protected version of them with an appropriateelectrophile.

[0178] The8-phenyl-6,9-dihydro-5H-pyrrolo[1,2,4]triazolo[4,3-c]pyrimidine-5-onederivatives of formula (I) can be converted by methods known per se intopharmaceutically acceptable salts, preferably acid addition salts bytreatment with organic or inorganic acids such as fumaric, tartaric,succinic or hydrochloric acid. Also8-phenyl-6,9-dihydro-5R-pyrrolo[1,2,4]triazolo[4,3-c]pyrimidine-5-onederivatives of formula (I) in which there is the presence of an acidicgroup, may be converted into pharmacologically acceptable salts byreaction with an alkali metal hydroxide or an organic base such assodium or potassium hydroxide. The acid or alkali addition salts soformed may be interchanged with suitable pharmaceutically acceptablecounter ions using process known per se.

[0179] The cyclic GMP specific phosphodiesterase (PEE 5) was isolatedfrom human platelet lysates by ion exchange chromatography using aMono-Q column. The enzyme activity was determined using 0.25 mM[3H]-cyclic GMP as substrate. The purification of the enzyme and theassessment of the PDE 5 inhibitory activity of our compounds wereperformed essentially as described by Gristwood et al., Br. J.Pharmacol. 1992, 105, 985-991.

[0180] The results are shown in Table 1. TABLE 1 Example IC₅₀ PDE5 (nM)11 0.099 24 0.042 34 0.22 41 0.17 45 0.21 50 0.15 58 0.3 71 0.12 73 0.3374 0.25 75 0.19 79 0.19

[0181] It can be seen from Table 1 that the compounds of formula (I) arepotent inhibitors of cyclic GMP specific phosphodiesterase (PDE 5).Preferred8-phenyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-oneand8-phenyl-6,9-dihydro-5H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-5-onederivatives of the invention possess an IC₅₀ value for the inhibition ofPDE 5 (determined as defined above) of less than 10 nM, preferably lessthan 5 nM and most preferably less than 1 nM. The8-phenyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-oneand8-phenyl-6,9-dihydro-5H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-5-onederivatives of the invention are useful in the treatment of stable,unstable and variant angina, hypertension, pulmonary hypertension,congestive heart failure, renal failure, atherosclerosis, conditions ofreduced blood vessel potency, peripheral vascular disease, followingExamples (including Preparation Examples (Preparations 1-8)) which donot limit the scope of the invention in any way.

[0182]¹H Nuclear Magnetic Resonance Spectra were recorded on a VarianGemini 300 spectrometer. Low Resolution Mass Spectra (m/z) were recordedon a Micromass ZMD mass spectrometer using ESI ionization. Meltingpoints were recorded using a Perkin Elmer DSC-7 apparatus. Thechromatographic separations were obtained using a Waters 2690 systemequipped with a Symmetry C18 (2.1×10 mm, 3.5 mM) column. The mobilephase was formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) andacetonitrile (500 mL) (B) and formic acid (0.46 mL), ammonia (0.115 mL)and water (1000 mL) (A): initially from 0% to 95% of B in 20 min, andthen 4 min. with 95% of B. The reequilibration time between twoinjections was 5 min. The flow rate was 0.4 mL/min. The injection volumewas 5 mL. Diode array chromatograms were collected at 210 nM.

PREPARATION EXAMPLES

[0183] Preparation 1

[0184] 8-(2-ethoxyphenyl)-6-propyl-6,9-dihydro-5S-pyrrolo[2,3-e3[1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0185] a) A solution of6-methyl-5-nitro-1-propyl-1H-pyrimidine-2,4-dione (8.23 g, 38.6 mmol),2-ethoxy benzaldehyde (8.1 mL, 57.92 mmol) and piperidine (5.73 mL,57.92 mmol) in ethanol (180 mL) with 3A molecular sieves (12.8 g) wasrefluxed for 4 hours. The resulting suspension was diluted withdichloromethane (100 mL), filtrated and the filtrates were evaporatedunder reduced pressure. The residue was suspended in water (100 mL) andacetic acid was added until pH was slightly acidic. The aqueoussuspension was partitioned between dichloromethane and brine, then theorganic phase was separated, washed with water, dried (MgSO₄) andevaporated under reduced pressure. The residue was vascular disorders(e.g. Raynaud's disease), stroke, bronchitis, chronic asthma, allergicasthma, allergic rhinitis, glaucoma, male erectile dysfunction, femalesexual dysfunction and diseases characterised by disorders of gutmotility, e.g. irritable bowel syndrome.

[0186] Accordingly, the B-phenyl-6,9-dihydro-5B-pyrrolo[2,3-e](1,2,4]triazolo[4,3-c]pyrimidine-5-one and8-phenyl-6,9-dihydro-5H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one derivatives of the invention andpharmaceutically acceptable salts thereof, and pharmaceuticalcompositions comprising such compound and/or salts thereof, may be usedin a method of treatment of disorders of the human body which comprisesadministering to a patient requiring such treatment an effective amountof a 8-phenyl-6,9-dihydro-5.-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one or8-phenyl-6,9-dihydro-5H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one derivative of the invention or apharmaceutically acceptable salt thereof.

[0187] The present invention also provides pharmaceutical compositionswhich comprise, as an active ingredient, at least a8-phenyl-6,9-dihydro-5H-pyrrolo[1,2,4]triazolo[4,3-c]pyrimidine-5-onederivative of formula (I) or a pharmaceutically acceptable salt thereofin association with a pharmaceutically acceptable excipient such as acarrier or diluent. The active ingredient may comprise 0.001% to 99% byweight, preferably 0.01% to 90% by weight of the composition dependingupon the nature of the formulation and whether further dilution is to bemade prior to application. Preferably the compositions are made up in aform suitable for oral, topical, nasal, rectal, percutaneous orinjectable administration.

[0188] The pharmaceutically acceptable excipients which are admixed withthe active compound, or salts of such compound, to form the compositionsof this invention are well-known per se and the actual excipients useddepend inter alia on the intended method of administering thecompositions.

[0189] Compositions of this invention are preferably adapted forinjectable and per os administration. In this case, the compositions fororal administration may take the form of tablets, retard tablets,sublingual tablets, capsules, inhalation aerosols, inhalation solutions,dry powder inhalation, or liquid preparations, such as mixtures,elixirs, syrups or suspensions, all containing the compound of theinvention; such preparations may be made by methods well-known in theart.

[0190] The diluents which may be used in the preparation of thecompositions include those liquid and solid diluents which arecompatible with the active ingredient, together with colouring orflavouring agents, if desired. Tablets or capsules may convenientlycontain between 2 and 500 mg of active ingredient or the equivalentamount of a salt thereof.

[0191] The liquid composition adapted for oral use may be in the form ofsolutions or suspensions. The solutions may be aqueous solutions of asoluble salt or other derivative of the active compound in associationwith, for example, sucrose to form a syrup. The suspensions may comprisean insoluble active compound of the invention or a pharmaceuticallyacceptable salt thereof in association with water, together with asuspending agent or flavouring agent.

[0192] Compositions for parenteral injection may be prepared fromsoluble salts, which may or may not be freeze-dried and which may bedissolved in pyrogen free aqueous media or other appropriate parenteralinjection fluid.

[0193] Effective doses are normally in the range of 10-600 mg of activeingredient per day. Daily dosage may be administered in one or moretreatments, preferably from 1 to 4 treatments, per day.

[0194] The syntheses of the compounds of the invention and of theintermediates for use therein are illustrated by the triturated withethyl ether and the precipitate collected by filtration and dried undervacuum to yield6-[(E)-2-(2-ethoxyphenyl)vinyl]-5-nitro-1-propyl-1H-pyrimidine-2,4-dione(10.24 g, 77%) as a yellow solid.

[0195] d(CDCl₃): 0.98 (t, 3H), 1.48 (t, 3H), 1.77 (m, 2H), 3.86 (t, 2H),4.11 (q, 2H), 6.95 (m, 3H), 7.36 (m, 3H).

[0196] b) To a stirred solution of the above compound (10.17 g, 29.44mmol) in formic acid (271 mL) was slowly added sodium dithionite (29.73g, 170.7 mmol) and the mixture was refluxed overnight. The resultingsolution was cooled to room temperature and poured into water (1.5 L).The precipitate was collected-by filtration and washed with water andethyl ether, then dried under vacuum to yield6-(2-Ethoxyphenyl)-1-propyl-1,5-dihydropyrrolo[3,2-d]pyrimidine-2,4-dione(7.73 g, 84%) as a white solid.

[0197] d(DMSO-d6): 0.96 (t, 3H), 1.42 (t, 3H), 1.73 (m, 2H), 3.80 (t,2H), 4.13 (q, 2H), 6.68 (s, 1H), 7.05 (t, 1H), 7.15 (d, 1H), 7.32 (t,1H), 7.81 (d, 1H), 10.86 (bs, 1H), 11.96 (bs, 1H).

[0198] c) Phosphorus pentasulphide (4.24 g, 19.14 mmol) was addedportionwise to a stirred suspension of the above compound (4 g, 12.76mmol) in pyridine (60 mL) and the resulting mixture stirred under refluxfor 3 hours, then evaporated under reduced pressure. The residue wastriturated with water and the precipitate collected by filtration anddried under vacuum to yield 6-(2-ethoxyphenyl)-1-propyl-4-thioxo-1,3,4,5-tetrahydropyrrolo[3,2-d]pyrimidin-2-one(4 g, 95%) as a yellow solid.

[0199] d) A stirred mixture of the above compound (4.2 g, 12.76 mmol)and hydrazine monohydrate (43 mL) was heated to 130° C. for 2 hours. Theresulting mixture was cooled and the precipitate collected by filtrationand washed with water and ethyl ether, then dried under vacuum to yield6-(2-ethoxyphenyl)-4-hydrazono-1-propyl-1,3,4,5-tetrahydropyrrolo[3,2-d]pyrimidin-2-one(3.17 g, 76%) as an off-white solid.

[0200] e) A stirred mixture of the above compound (3.17 g, 9.68 mmol)and formic acid (32 mL) was heated under reflux for 2 hours. Theresulting solution was concentrated under vacuum and the residuepartitioned between dichloromethane and aqueous sodium bicarbonatesolution, then the organic phase separated, washed with water, dried(MgSO₄) and evaporated under reduced pressure to yield 8-(2-ethoxyphenyl)-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one (3.11 g, 95%) as a yellowish solid.

[0201] d(CDCl₃): 1.05 (t, 3H), 1.65 (t, 3H), 1.91 (m, 2H), 4.16 (t, 2H),4.34 (q, 2H), 6.58 (s, 1H), 7.06 (m, 2H), 7.35 (m, 1H), 7.74 (d, 1H),8.97 (s, 1H), 10.79 (bs, 1H).

[0202] Preparation 2

[0203] 4-Ethoxy-3-(5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzenesulfonyl Chloride

[0204] The title compound of Preparation 1 (2 g, 5.92 mmol) was addedportionwise to a mixture of chlorosulfonic acid (10 mL) and thionylchloride (1 mL) and stirred at 0° C. for 45 minutes. The reactionmixture was carefully poured into stirred ice-water and the aqueoussuspension was partitioned between dichloromethane and brine, then theorganic phase was separated, washed with water, dried (MgSO₄) andevaporated under reduced pressure to yield the title product (2.5 g,90%) as a white solid.

[0205] Preparation 3

[0206] 3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-ethoxybenzene Sulfonyl Chloride

[0207] The title compound of Preparation 1 (0.7 g, 2.07 mmol) was addedportionwise to a mixture of chlorosulfonic acid (3.5 mL) and sulfurylchloride (1.75 mL) and stirred at 0° C. for 2 hours. The reactionmixture was carefully poured into stirred ice-water and the aqueoussuspension was partitioned between dichloromethane and brine, then theorganic phase was separated, washed with water, dried (MgSO₄) andevaporated under reduced pressure to yield the title compound (0.9 g,93%) as a yellowish solid.

[0208] d(CDCl₃): 1.05 (t, 3H), 1.38 (t, 3H), 1.90 (m, 2H), 4.21 (q, 2H),4.48 (t, 3H), 7.18 (d, 1H), 8.12 (dd, 1H), 8.37 (d, 1H), 8.81 (s, 1H),12.98 (bs, 1H).

[0209] Preparation 4

[0210] 3-(7-Bromo-5-oxo-6-propyl-6,9-dihydro-5Sl-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-ethoxybenzene Sulfonyl Chloride

[0211] To a solution of the title compound of Preparation 2 (0.24 g,0.55 mmol) in glacial acetic acid (5 mL), was slowly added bromine(0.033 mL, 0.64 mmol) and the mixture was stirred at room temperaturefor 1 hour. Then the reaction mixture was poured into ice-water andpartitioned between dichloromethane and brine, the organic phase wasseparated, dried (MgSO₄) and evaporated under reduced pressure to yieldthe title product (0.21 g, 75%).

[0212] Preparation 5

[0213] B-(2-Propoxyphenyl)-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0214] Obtained as a white solid (50% overall) from6-methyl-5-nitro-1-propyl-1H-pyrimidine-2,4-dione and2-propoxybenzaldehyde following the procedure described in Preparation1.

[0215] d(DMSO-d6): 1.02 (m, 6H), 1.82 (m, 4H), 4.03 (m, 4H), 6.91 (s,1H), 7.10 (m, 2H), 7.35 (t, 1H), 7.91 (d, 1H), 9.18 (s, 1H), 12.58 (bs,1H).

[0216] Preparation 6

[0217] 3-(5-Oxo-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxybenzenesulfonyl Chloride

[0218] Obtained as a white solid (80%) from the title compound ofPreparation 5, using the procedure described in Preparation 2.

[0219] d(CDCl₃): 1.10 (m, 6H), 2.03 (m, 4H), 4.21 (t, 2H), 4.52 (t, 2H),6.75 (s, 1H), 7.22 (d, 1H), 8.05 (dd, 1H), 8.38 (d, 1H), 8.88 (s, 1H),12.50 (bs, 1H).

[0220] Preparation 7

[0221] 3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5S-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxybenzene Sulfonyl Chloride

[0222] Obtained as a yellowish solid (90%) from the title compound ofPreparation 5, using the procedure described in Preparation 3.

[0223] d(DMSO-d6): 0.93 (m, 6H), 1.70 (m, 4H), 3.99 (t, 2H), 4.35 (t,2H), 7.17 (d, 1H), 7.60 (d, 1H), 7.65 (dd, 1H), 9.27 (s, 1H), 13.2 (bs,1H).

[0224] Preparation 8

[0225] 3-(7-Bromo-5-oxo-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxybenzenesulfonyl Chloride

[0226] Obtained as a white solid (92%) from the title compound ofPreparation 6, using the procedure described in Preparation 4.

[0227] d(CDCl₃): 0.98 (t, 3H), 1.10 (t, 3H), 1.88 (m, 4H), 4.15 (t, 2H),4.58 (t, 2H), 7.21 (d, 1H), 8.12 (dd, 1H), 8.30 (d, 1H), 8.88 (s, 1H),12.85 (bs, 1H).

[0228] Preparation 9

[0229] 3-(7-Iodo-5-oxo-6-propyl-6,9-dihydro-5B-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxybenzenesulfonyl Chloride

[0230] To a solution of the title compound of Preparation 6 (0.77 g,1.71 mmol) in glacial acetic acid (5 mL), was slowly added iodinemonochloride (0.18 mL, 3.42 mmol) and the mixture was stirred at roomtemperature for 2 hours. Then the reaction mixture was poured intoice-water and partitioned between dichloromethane and brine, the organicphase was separated, dried (MgSO₄) and evaporated under reduced pressureto yield the title product (0.83 g, 84%).

[0231] d(CDCl₃): 0.98 (t, 3H), 1.10 (t, 3H), 1.89 (m, 4H), 4.18 (t, 2H),4.60 (t, 2H), 7.22 (d, 1H), 8.16 (dd, 1H), 8.22 (d, 1H), 8.82 (s, 1H),12.60 (bs, 1H).

EXAMPLES

[0232] TABLE 2

(I) Example No R¹ R² R³ R⁶ NR⁴R⁵ 1 H nPr Et H

2 H nPr Et H

3 H nPr Et H

4 H nPr nPr H

5 H nPr nPr H

6 H nPr nPr H

7 H nPr nPr H

8 H nPr nPr H

9 H nPr Et Cl

10 H nPr Et Cl

11 H nPr Et Cl

12 H nPr Et Cl

13 H nPr Et Cl

14 H nPr Et Cl

15 H nPr Et Cl

16 H nPr Et Cl

17 H nPr Et Cl

18 H nPr Et Cl

19 H nPr Et Cl

20 H nPr Et Cl

21 H nPr Et Cl

22 H nPr Et Cl

23 H nPr Et Cl

24 H nPr Et Cl

25 H nPr nPr Cl

26 H nPr nPr Cl

27 H nPr nPr Cl

28 H nPr nPr Cl

29 H nPr nPr Cl

30 H nPr nPr Cl

31 H nPr nPr Cl

32 H nPr nPr Cl

33 H nPr nPr Cl

34 H nPr nPr Cl

35 H nPr nPr Cl

36 H nPr nPr Cl

37 H nPr nPr Cl

38 H nPr nPr Cl

39 H nPr nPr Cl

40 H nPr nPr Cl

41 H nPr nPr Cl

42 H nPr nPr Cl

43 H nPr nPr Cl

44 H nPr nPr Cl

45 H nPr nPr Cl

46 H nPr nPr Cl

47 H nPr nPr Cl

48 H nPr nPr Cl

49 H nPr nPr Cl

50 H nPr nPr Cl

51 H nPr nPr Cl

52 H nPr Et Br

53 H nPr Et Br

54 H nPr Et Br

55 H nPr Et Br

56 H nPr Et Br

57 H nPr nPr Br

58 H nPr nPr Br

59 H nPr nPr Br

60 H nPr nPr Br

61 H nPr nPr Br

62 H nPr nPr Br

63 H nPr nPr Br

64 H nPr nPr Br

65 H nPr nPr Br

66 H nPr nPr Br

67 H nPr nPr Br

68 H nPr nPr Br

69 H nPr nPr Br

70 H nPr nPr Br

71 H nPr nPr Br

72 H nPr nPr Br

73 H nPr nPr Br

74 H nPr nPr Br

75 H nPr Et Cl

76 H nPr Et Cl

77 H nPr Et Cl

78 H nPr Et Cl

79 H nPr Et Cl

80 H nPr nPr Br

81 H nPr nPr Br

82 H nPr nPr Br

83 H nPr nPr Br

84 H nPr nPr I

85 H nPr nPr I

86 H nPr nPr I

87 H nPr nPr I

88 H nPr nPr I

Example 1

[0233]8-[2-ethoxy-5-(4-ethylpiperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0234] To a mixture of the title compound of Preparation 2 (50 mg, 0.115mmol) and polymer bound morpholine (85 mg, 2.75 mmol/g based on nitrogenanalysis) in dichloromethane (3 mL) was added 1-ethylpiperazine (0.016mL, 0.126 mmol) and the resulting mixture was stirred at roomtemperature overnight. The reaction mixture was filtered and thefiltrate was evaporated under reduced pressure. The residue wastriturated with diethyl ether and the precipitate was collected byfiltration and dried under vacuum to yield the title compound (49 mg,83%) as a white solid.

[0235] ESI/MS m/e: 514 ([M+H]⁺, C₂₄H₃₁N₇O₄S)

[0236] Retention Time (min.): 11.6

Examples 2-3

[0237] The compounds of this invention were synthesized from the titlecompound of Preparation 2 following the procedure of example 1 and usingthe corresponding reactant respectively. The ESI/MS data, HPLC retentiontimes and yields are summarised in Table 3. TABLE 3 ESI/MS RetentionMolecular m/e Time Example Formula [M + H]⁺ (min.) Yield % 2 C₂₄H₃₁N₇O₅S530 11.6 75 3 C₂₃H₂₉N₇O₄S 500 11.6 86

Examples 4-8

[0238] The compounds of this invention were synthesized from the titlecompound of Preparation 6 following the procedure of example 1 and usingthe corresponding reactant respectively. The ESI/MS data, HPLC retentiontimes and yields are summarised in Table 4. TABLE 4 ESI/MS RetentionMolecular m/e Time Example Formula [M + H]⁺ (min.) Yield % 4 C₂₅H₃₃N₇O₄S528 12.1 78 5 C₂₅H₃₃N₇O₄S 528 12.0 80 6 C₂₅H₃₃N₇O₅S 544 11.8 75 7C₂₅H₃₃N₇O₅S 544 12.1 77 8 C₂₄H₃₁N₇O₄S 514 12.0 72

Examples 9-24

[0239] The compounds of this invention were synthesized from the titlecompound of Preparation 3 following the procedure of example 1 and usingthe corresponding reactant respectively. The ESI/MS data, HPLC retentiontimes and yields are summarised in Table 5. TABLE 5 ESI/MS RetentionMolecular m/e Time Example Formula [M + H]⁺ (min.) Yield %  9C₂₂H₂₆ClN₇O₄S 520 12.0 75 10 C₂₄H₃₀ClN₇O₄S 548 12.0 78 11 C₂₄H₃₀ClN₇O₄S548 11.8 80 12 C₂₄H₃₀ClN₇O₅S 564 11.7 78 13 C₂₄H₃₀ClN₇O₅S 564 12.0 77 14C₂₅H₃₂ClN₇O₅S 578 12.0 81 15 C₂₃H₂₈ClN₇O₄S 534 12.0 77 16 C₂₄H₃₀ClN₇O₄S548 12.3 67 17 C₂₁H₂₁ClN₆O₄S 488 16.3 32 18 C₂₅H₃₀ClN₇O₄S 560 13.2 72 19C₂₅H₃₂ClN₇O₄S 562 12.5 80 20 C₂₅H₃₂ClN₇O₅S 578 12.8 85 21 C₂₅H₃₂ClN₇O₄S562 12.7 68 22 C₂₃H₂₈ClN₇O₄S 534 12.4 65 23 C₂₅H₃₂ClN₇O₅S 578 12.0 75 24C₂₆H₃₄ClN₇O₅S 592 13.2 76

Examples 25-51

[0240] The compounds of this invention were synthesized from the titlecompound of Preparation 7 following the procedure of example 1 and usingthe corresponding reactant respectively. The ESI/MS data, HPLC retentiontimes and yields are summarised in Table 6. TABLE 6 ESI/MS RetentionMolecular m/e Time Example Formula [M + H]⁺ (min.) Yield % 25C₂₃H₂₈ClN₇O₄S 534 12.6 70 26 C₂₃H₂₇ClN₆O₅S 535 17.7 65 27 C₂₅H₃₂ClN₇O₄S562 12.7 68 28 C₂₃H₃₀ClN₇O₄S 536 12.2 62 29 C₂₅H₃₂ClN₇O₄S 562 12.5 75 30C₂₅H₃₂ClN₇O₅S 578 12.4 69 31 C₂₅H₃₂ClN₇O₅S 578 12.7 62 32 C₂₆H₃₄ClN₇O₄S576 12.6 81 33 C₂₆H₃₄ClN₇O₅S 592 12.3 65 34 C₂₆H₃₄ClN₇O₅S 592 12.7 78 35C₂₆H₂₈ClN₇O₄S 570 15.5 75 36 C₂₄H₃₁ClN₈O₄S 563 12.3 66 37 C₂₄H₂₈ClN₇O₅S562 16.6 70 38 C₂₆H₃₄ClN₇O₅S 592 13.2 70 39 C₂₄H₃₀ClN₇O₄S 548 12.7 74 40C₂₆H₃₄ClN₇O₄S 576 13.3 57 41 C₂₈H₃₈ClN₇O₄S 604 12.9 62 42 C₂₂H₂₃ClN₆O₄S502 17.2 15 43 C₂₆H₃₄ClN₇O₄S 576 12.8 52 44 C₂₇H₃₆ClN₇O₅S 606 13.8 70 45C₂₆H₃₂ClN₇O₄S 574 13.8 68 46 C₂₆H₃₄ClN₇O₄S 576 13.1 69 47 C₂₄H₃₀ClN₇O₄S548 13.2 45 48 C₂₆H₃₃ClN₆O₅S 577 19.3 53 49 C₂₁H₂₅ClN₆O₄S 492 18.0 59 50C₂₁H₂₅ClN₆O₅S 508 16.0 44 51 C₂₄H₃₂ClN₇O₄S 550 12.7 78

Examples 52-56

[0241] The compounds of this invention were synthesized from the titlecompound of Preparation 4 following the procedure of example 1 and usingthe corresponding reactant respectively. The ESI/MS data, HPLC retentiontimes and yields are summarised in Table 7. TABLE 7 ESI/MS RetentionMolecular m/e Time Example Formula [M + H]⁺ (min.) Yield % 52C₂₂H₂₆BrN₇O₄S 565 12.4 63 53 C₂₄H₃₀BrN₇O₄S 593 12.4 75 54 C₂₄H₃₀BrN₇O₅S609 12.1 82 55 C₂₄H₃₀BrN₇O₅S 609 12.4 79 56 C₂₃H₂₈BrN₇O₄S 579 12.4 80

Examples 54-72

[0242] The compounds of this invention were synthesized from the titlecompound of Preparation 8 following the procedure of example 1 and usingthe corresponding reactant respectively. The ESI/MS data, HPLC retentiontimes and yields are summarised in Table 8. TABLE 8 ESI/MS RetentionMolecular m/e Time Example Formula [M + H]⁺ (min.) Yield % 57C₂₅H₃₂BrN₇O₄S 606 12.8 66 58 C₂₄H₃₀BrN₇O₄S 592 12.7 75 59 C₂₂H₂₃BrN₆O₄S547 17.1 70 60 C₂₁H₂₅BrN₆O₄S 537 17.8 66 61 C₂₃H₂₇BrN₆O₅S 579 17.7 60 62C₂₅H₃₂BrN₇O₄S 606 13.0 52 63 C₂₅H₃₂BrN₇O₅S 622 12.9 78 64 C₂₆H₃₄BrN₇O₅S636 13.7 80 65 C₂₈H₃₈BrN₇O₄S 648 13.1 85 66 C₂₆H₃₄BrN₇O₄S 620 16.7 78 67C₂₆H₃₂BrN₇O₄S 618 14.1 56 68 C₂₆H₃₄BrN₇O₄S 620 13.3 82 69 C₂₄H₃₀BrN₇O₄S592 13.4 42 70 C₂₅H₃₂BrN₇O₄S 606 13.0 45 71 C₂₆H₃₄BrN₇O₅S 636 13.0 80 72C₂₅H₃₂BrN₇O₄S 606 13.3 48

Example 73

[0243]7-Bromo-8-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0244] To a mixture of the title compound of Preparation 8 (0.6 g, 1.14mmol) and triethylamine (0.175 mL, 1.25 mmol) in dichloromethane (30 mL)was added dropwise 1-(2-hydroxy ethyl)piperazine (0.163 g, 1.25 mmol)and the resulting mixture was stirred at room temperature overnight. Thereaction mixture was diluted with dichloromethane, washed with aqueoussolution of sodium bicarbonate in water, dried (MgSO₄) and evaporatedunder reduced pressure. The resulting crude residue was triturated withhot methanol and the precipitate collected by filtration and dried undervacuum to yield the title compound (270 mg, 38%).

[0245] m.p.: 2671C

[0246] d(DMSO-d6): 0.98 (m, 6H), 1.74 (m, 4H), 2.38 (t, 2H), 2.50 (m,4H), 2.92 (m, 4H), 3.44 (q, 2H), 4.09 (t, 2H), 4.36 (m, 3H), 7.41 (d,1H), 7.65 (d, 1H), 7.81 (dd, 1H), 9.21 (s, 1H), 13.32 (bs, 1H).

Example 74

[0247]7-Bromo-8-[5-(piperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one

[0248] Obtained as a white solid (15%) from the title compound ofPreparation 8 and piperazine following the procedure of example 73.

[0249] m.p.: 2451C

[0250] d(DMSO-d6): 0.95 (m, 6H), 1.75 (m, 4H), 2.75 (m, 4H), 2.84 (m,4H), 4.10 (t, 2H), 4.35 (t, 2H), 7.41 (d, 1H), 7.65 (d, 1H), 7.79 (dd,1H), 9.21 (s, 1H), 13.2 (bs, 1H).

Examples 75-79

[0251] The compounds of this invention were synthesized from the titlecompound of Preparation 3 following the procedure of example 1 and usingthe corresponding reactant respectively. The ESI/MS data, HPLC retentiontimes and yields are summarised in Table 9. TABLE 9 ESI/MS RetentionMolecular m/e Time Example Formula [M + H]⁺ (min.) Yield % 75C₂₅H₃₀ClN₇O₄S 560 8.2 65 76 C₂₅H₃₀ClN₇O₄S 560 8.3 72 77 C₂₆H₃₂ClN₇O₄S574 8.1 75 78 C₂₅H₃₀ClN₇O₅S 576 8.2 42 79 C₂₄H₂₈ClN₇O₄S 546 7.9 60

Examples 80-83

[0252] The compounds of this invention were synthesized from the titlecompound of Preparation 8 following the procedure of example 1 and usingthe corresponding reactant respectively. The ESI/MS data, HPLC retentiontimes and yields are summarised in Table 10. TABLE 10 ESI/MS RetentionMolecular m/e Time Example Formula [M + H]⁺ (min.) Yield % 80C₂₆H₃₂BrN₇O₄S 619 8.8 82 81 C₂₇H₃₄BrN₇O₄S 633 8.7 78 82 C₂₆H₃₂BrN₇O₅S635 8.9 51 83 C₂₅H₃₀BrN₇O₄S 605 8.5 88

Examples 84-88

[0253] The compounds of this invention were synthesized from the titlecompound of Preparation 9 following the procedure of example 1 and usingthe corresponding reactant respectively. The ESI/MS data, HPLC retentiontimes and yields are summarised in Table 11. TABLE 11 ESI/MS RetentionMolecular m/e Time Example Formula [M + H]⁺ (min.) Yield % 84C₂₆H₃₂IN₇O₄S 666 8.5 77 85 C₂₆H₃₂IN₇O₄S 666 8.5 85 86 C₂₇H₃₄IN₇O₄S 6808.5 62 87 C₂₆H₃₂IN₇O₅S 682 8.8 35 88 C₂₅H₃₀IN₇O₄S 652 8.4 75

[0254] The following examples illustrate pharmaceutical compositionsaccording to the present invention and procedures for their preparation.

Composition Example 1

[0255] 50,000 capsules each containing 100 mg of active ingredient wereprepared according to the following formulation: Active ingredient   5Kg Lactose monohydrate  10 Kg Colloidal silicone dioxide 0.1 Kg Cornstarch   1 Kg Magnesium stearate 0.2 Kg

[0256] Procedure

[0257] The above ingredients were sieved through a 60 mesh sieve, andwere loaded into a suitable mixer and filled into 50,000 gelatinecapsules.

Composition Example 2

[0258] 50,000 Tablets each containing 50 mg of active ingredient wereprepared from the following formulation: Active ingredient  2.5 KgMicrocrystalline cellulose 1.95 Kg Spray dried lactose 9.95 KgCarboxymethyl starch  0.4 Kg Sodium stearyl fumarate  0.1 Kg Colloidalsilicon dioxide  0.1 Kg

[0259] Procedure

[0260] All the powders were passed through a screen with an aperture of0.6 mm, then mixed in a suitable mixer for 20 minutes and compressedinto 300 mg tablets using 9 mm disc and flat bevelled punches. Thedisintegration time of the tablets was about 3 minutes.

1. A compound of formula (I):

wherein: —X—C—Y— represents

R¹, R² and R³ each independently represent: hydrogen; an alkyl groupwhich is unsubstituted or substituted by hydroxy, alkoxy, alkylthio,amino, mono- or di-alkylamino, hydroxycarbonyl, alkoxycarbonyl,acylamino, carbamoyl or alkylcarbamoyl groups; or a group of formula—(CH₂)_(n)—R⁷ wherein n is an integer from 0 to 4 and R⁷ represents: acycloalkyl group which may be unsubstituted or substituted by one ormore halogen atoms or alkyl, hydroxy, alkylenedioxy, alkoxy, amino,mono- or di-alkylamino, alkylamido, nitro, cyano or trifluoromethylgroups; a phenyl group which may be unsubstituted or substituted by oneor more halogen atoms or alkyl, hydroxy, alkylenedioxy, alkoxy, amino,mono- or di-alkylamino, nitro, cyano or -trifluoromethyl groups; or a 3to 7-membered ring comprising from 1 to 4 heteroatoms selected fromnitrogen, oxygen and sulphur, which ring may be unsubstituted orsubstituted by one or more halogen atoms or hydroxy, alkoxy, phenyl,alkoxycarbonyl, amino, mono-alkylamino, di-alkylamino or hydroxycarbonylgroups or one or more alkyl groups which may be unsubstituted orsubstituted by one or more halogen atoms or hydroxy, alkoxy,hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, mono- or di-alkylamino orhydroxycarbonyl groups, either R⁴ and R⁵ together with the nitrogen atomto which they are attached form a 3 to 7-membered ring comprising atotal of from 1 to 4 heteroatoms selected from nitrogen, oxygen andsulphur, which ring may be unsubstituted or substituted by one or morehalogen atoms or hydroxy, oxoalkyl, carbamoyl, hydroxycarbonyl,alkoxycarbonyl, trifluoroacetyl, amino, mono- or di-alkylamino groupsand/or an alkylene group and/or one or more alkyl groups, wherein saidalkylene group and said alkyl groups may in turn be unsubstituted orsubstituted by one or more hydroxy, alkoxy, hydroxyalkoxy, amino ormono- or di-alkylamino groups, or R⁴ and R⁵ independently representhydrogen, an amidino group or an alkyl, alkenyl or alkynyl group whichmay be unsubstituted or substituted by one or more halogen atoms orhydroxy, alkoxy, alkylthio, amino, mono- or di-alkylamino groups, or R⁴represents hydrogen or an alkyl group and R⁵ represents a group offormula —(CH₂), —R⁷ wherein n and R⁷ are defined above, and R⁶represents a hydrogen or halogen atom, or a nitro or alkoxycarbonylgroup, or an alkyl group which is unsubstituted or substituted by one ormore hydroxy, alkoxy, alkylthio, amino, mono- or di-alkylamino,hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl or alkylcarbamoylgroups, or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1 wherein R¹ represents: hydrogen; a C₁-C₄ alkylgroup; or a group of formula —(CH₂)_(n)R⁷ wherein n is 0, 1 or 2 and R⁷represents phenyl, pyridyl or morpholinyl.
 3. A compound according toclaim 1 or claim 2 wherein R² represents: a C₁-C₅ alkyl group; asubstituted C₁-C₅ alkyl group; a C₃₋₁₀ cycloalkyl group; or a group offormula —(CH₂)_(n)R⁷ wherein n is 0, 1 or 2 and R⁷ represents anunsubstituted or substituted phenyl or pyridyl group.
 4. A compoundaccording to any one of the preceding claims wherein R³ represents: aC₁-C₄ alkyl group; a C₃₋₁₀ cycloalkyl group; or a group of formula—(CH₂)_(n)R⁷ wherein n is 0, 1 or 2 and R⁷ represents an unsubstitutedor substituted phenyl or pyridyl group.
 5. A compound according to anyone of the preceding claims wherein R⁴ and R⁵ together with the nitrogenatom to which they are attached form a piperidyl, pyrrolidyl,azetidinyl, aziridyl, piperazinyl, [1,4]diazepan-1-yl, morpholinyl,thiomorpholinyl, pyrrolyl, pyrazolyl, imidazolyl, imidazolidinyl,pyrazolinyl, indolinyl or isoindolinyl group, which is unsubstituted orsubstituted by an alkylene group and/or from 1 to 3 groups independentlyselected from C₁-C₄ alkyl, C₂-C₄ alkenyl, carbamoyl, amino,di-C₁-C₄-alkylamino, (2-hydroxyethyl)methylamino, hydroxyl,2,2,2-trifluoroethanoyl, 2,2,2-trifluoroethyl, carbaldehyde groups andhydroxyalkyl groups, alkoxycarbonyl groups, alkoxyalkyl groups andhydroxyalkoxyalkyl groups wherein the alkyl moieties contain from 1 to 4carbon atoms, and wherein said alkylene group may in turn beunsubstituted or substituted by one or more hydroxy, alkoxy,hydroxyalkoxy, amino or mono- or di-alkylamino groups.
 6. A compoundaccording to any one of claims 1 to 4 wherein R⁴ and R⁵ independentlyrepresent hydrogen or a propynyl group, an amidino group or a C₁-C₄alkyl group which is unsubstituted or substituted by a hydroxy, methylor dimethylamino group.
 7. A compound according to any one of claims 1to 4 wherein wherein R⁵ is a group of formula —(CH₂)_(n)R⁸ wherein n is0, 1, 2 or 3 and R⁸ is a pyridyl, piperidyl, piperazinyl, morpholinyl,triazolyl, tetrazolyl, pyrrolidinyl, 1-ethylaminocyclohex-1-yl,1-diethylaminocyclohex-1-yl, 1-ethylaminocyclohept-1-yl,1-diethylaminocyclohept-1-yl, 3,4-dimethoxyphenyl,1-methyl-4-phenylpiperidin-4-yl, imidazoyl, 1-methylpiperid-4-yl,tetrahydrofuranyl, 2,2,6,6,-tetramethylpiperid-4-yl,4-hydroxypiperid-4-yl, 1-acetamidocyclohept-1-yl, 1-methyl-3-azetidinylor 4-methylpiperazin-1-yl group.
 8. A compound according to any one ofthe preceding claims wherein R⁶ represents a fluorine, chlorine, bromineor hydrogen atom or a methyl, ethyl, n-propyl, n-butyl, methoxycarbonyl,ethoxycarbonyl, or nitro group.
 9. A compound according to any one ofthe preceding claims characterised in that it has an IC₅ value for theinhibition of PDE 5 of less than 10 nM.
 10. A compound according toclaim 1 which is:7-Chloro-8-[2-ethoxy-5-(4-methyl-[1,4]diazepane-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one7-Chloro-8-{2-ethoxy-5-[4-(2-ethoxyethyl)piperazine-1-sulfonyl]phenyl}-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one7-Chloro-8-{5-[4-(3-hydroxypropyl)piperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-4-propoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzenesulfonamide8-[5-(4-Allylpiperazine-1-sulfonyl)-2-propoxyphenyl]-7-chloro-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one3-(7-Chloro-5-oxo-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-(2-hydroxyethyl)-4-propoxybenzenesulfonamide7-Bromo-8-[5-(4-methylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one 47-Bromo-8-{5-[4-(2-Hydroxyethyl)-[1,4]diazepane-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one7-Bromo-8-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro-5R-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one7-Bromo-8-[5-(piperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro-5H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-5-one or a pharmaceutically acceptable salt thereof.
 11. Aprocess for producing a compound of formula (I):

wherein: —X—C—Y— represents

R¹, R², R³, R⁴, R¹ and R⁶ are as defined in claim 1, which processcomprises reacting a compound of formula (IV):

wherein R¹, R², R³ and R⁶ are as defined in claim 1 with an amine offormula (V):

wherein R⁴ and R⁵ are as defined in claim
 1. 12. A process for producinga compound of formula (I):

wherein: —X—C—Y— represents

and R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in claim 1, which processcomprises reacting a compound of formula (XIII):

wherein R², R³, R⁴, R¹ and R⁶ are as defined in claim 1 with acarboxylic acid of formula (VIII): R¹—COOH  (VIII) wherein R¹ is asdefined in claim 1, or a reactive derivative thereof.
 13. A compound offormula (VI):

wherein R¹, R², R³ and R⁶ are as defined in claim
 1. 14. A compound offormula(IX):

wherein R², R³ and R⁶ are as defined in claim
 1. 15. A compound offormula (XIV):

wherein R², R³, R⁴, R¹ and R⁶ are as defined in claim
 1. 16. Use of acompound as defined in any one of claims 13 to 15 as an intermediate inthe production of a compound according to claim
 1. 17. A pharmaceuticalcomposition comprising as an active ingredient, at least one compound asdefined in any one of claims 1 to 10 or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable excipient.
 18. A compoundaccording to any one of claims 1 to 10 or a composition according toclaim 17 for use in a method of treatment of the human or animal body.19. Use of a compound according to any one of claims 1 to 10 in themanufacture of a medicament for the treatment of stable, unstable andvariant angina, hypertension, pulmonary hypertension, congestive heartfailure, renal failure, atherosclerosis, conditions of reduced bloodvessel potency, peripheral vascular disease, vascular disorders, stroke,bronchitis, chronic asthma, allergic asthma, allergic rhinitis,glaucoma, male erectile dysfunction, female sexual dysfunction anddiseases characterised by disorders of gut motility.
 20. A method oftreating a human or animal patient suffering from stable, unstable andvariant angina, hypertension, pulmonary hypertension, congestive heartfailure, renal failure, atherosclerosis, conditions of reduced bloodvessel potency, peripheral vascular disease, vascular disorders, stroke,bronchitis, chronic asthma, allergic asthma, allergic rhinitis,glaucoma, male erectile dysfunction, female sexual dysfunction ordiseases characterised by disorders of gut motility, which methodcomprises administering to said patient in need of such treatment aneffective amount of a compound as defined in claim 1.